Experimental autoimmune encephalomyelitis (EAE) is a relapsing- remitting demyelinating disease of the central nervous system (CNS) that serves as an animal model for multiple sclerosis (MS). Disease induction is accompanied by CNS histopathology characterized by mononuclear cell infiltrates, consisting of T cells, macrophages, and B cells. The CNS infiltration by macrophages, T cells, and B cells results in chronic relapsing remitting paralysis similar to what has been seen in a subset of MS patients. One o the major goals of this application is to address the role of chemokines and chemokine receptors in PLP-induced EAE, including determining the chemokines that are important in development of active and adoptive EAE, as well as during acute EAE, remission, and relapses of EAE. The relative role of specific chemokines in the CNS recruitment of antigen specific T cells as well as non-specific T cells and macrophages will be investigated. Furthermore, chemokines have been shown to have immune altering effects such as T cell co-stimulation, T cell cytokine expression, and T cell differentiation. Therefore, the role of chemokines in regulating the ongoing immune response in EAE will also be determined. We hypothesize that a temporal CNS expression pattern of selective chemokines and chemokine receptor regulates the immunopathogenesis of acute and relapsing EAE. This regulation includes effects on mononuclear cell chemoattraction as well as immunomodulation of cytokine responses. The following specific aims will be addressed to test our hypothesis: 1) Determination of chemokine regulation of acute and relapsing EAE induction and progression; 2) The role of CC chemokines in the immunomodulation of pro-inflammatory and anti-inflammatory cytokine responses during acute and relapsing EAE. These studies will help to understand the immunopathogenesis of MS and provide a basis for the development of novel chemokine and chemokine receptor therapies designed at targeting molecules involved in the migration of pathogenic lymphocytes into the CNS during the induction and progression of inflammatory demyelinating diseases.